Absorbable coating and blend

ABSTRACT

Absorbable coating and absorbable blend of polycaprolactone and crystallization modifier especially suitable for use in the coating of surgical sutures and in the controlled release of chemical or pharmaceutical agents.

This application is a division of application Ser. No. 07/944,861, filedSep. 14, 1992, now U.S. Pat. No. 5,380,780, issued on Jan. 10, 1995,which was a continuation of application Ser. No. 07/291,486, filed Dec.29, 1988, now abandoned.

BACKGROUND OF THE INVENTION

The present invention pertains generally to absorbable coatings andabsorbable blends for surgical sutures and drug delivery systems. Moreparticularly, the invention relates to absorbable compositions whichmight include a homopolymer of .di-elect cons.-caprolactone and acrystallization modifier or a copolymer of .di-elect cons.-caprolactone,an absorbable monomer, and a crystallization modifier.

During the past thirty years, the use of synthetic absorbable polymersin medical devices and drug delivery systems has made a dramatic rise.Foremost in the area of absorbable medical devices has been the usage ofabsorbable polyesters that are usually aliphatic and linear. Forexample, in the area of wound closure, there has been extensiveapplication of the homopolymer poly(glycolic acid), see for example U.S.Pat. No. 3,297,033, and copolymers of glycolic acid with a variety ofother monomers which produce likewise absorbable polymers, see forexample U.S. Pat. No. 3,839,297.

Dependent upon the specific application, there is a preferred timewindow where the synthetic polymer has completely absorbed, that is, haslost all of its mass to the surrounding tissue. In the case ofabsorbable sutures in sewn tissue after surgery, that window is usuallywithin one year, although even shorter times are more preferable (U.S.Pat. Nos. 4,027,676 and 4,201,216). For other applications this timewindow could be either shorter or longer. Thus, for a given applicationthere is a need to use absorbable polymers that degrade within the timelimits of that application.

There is some leeway in the selection of synthetic absorbable polyestersfor a given application since the rates of the hydrolysis of this classof polymers do vary over a wide range. Differences in the rates ofhydrolysis of absorbable synthetic polyesters can be attributed to theintrinsic hydrolytic stability of their specific ester linkages and tothe physical properties of their respective polymers. For instance, thehydrolytic stability of the ester linkage is strongly influenced by bothelectronic and steric factors. An example of an electronic effect is theincreased reactivity of ester linkages which have a hydroxy substitution∝ to the ester linkage, as in the case of esters of glycolic acid.Physical properties which are important to the hydrolytic behavior andsubsequent mass loss in synthetic absorbable polyesters include theglass transition temperature and the degree of crystallization in thepolymer. In semi-crystalline polymers like poly(glycolic acid) andpolycaprolactone, it has been hypothesized that hydrolysis takes placeinitially in the amorphous areas of the polymer, where migration orabsorption of the water molecule is facile compared to the crystallineareas. Thus it appears that the water molecule prior to reaction at anester linkage of a synthetic absorbable polyester must first have accessor absorption into the polymer. Crystalline areas of the polymer havebeen hypothesized to impede the access or penetration of watermolecules. Therefore, to the extent that this takes place, the overallhydrolytic breakdown of the absorbable polyester is retarded. In thecase of polycaprolactone, the hydrolytic degradation rate and subsequentmass loss is also dependent upon particle size, wherein small particlesdegrade and lose mass much more rapidly than a polymer cast in filmform.

One application of synthetic polyesters is in the coating of surgicalsutures. The coating on a surgical suture is very important in providinggood knotting performance, as explained in U.S. Pat. No. 3,390,681,where the snug down performance of a braided non-absorbablepoly(ethylene terephthalate) suture under both dry and wet conditionswas improved by deposition of small particles of non-absorbablepolytetrafluoroethylene. Tie-down performance of braided polyethyleneterephthalate has also been disclosed to be improved through its coatingwith linear polyesters (U.S. Pat. No. 3,942,532) such aspolycaprolactone. It was further disclosed in U.S. Pat. No. 3,942,532that polycaprolactone of molecular weight in the range of 1,000 to15,000 may also be used to coat synthetic absorbable sutures. However,polycaprolactone is known to be a slowly absorbable synthetic polyester,that may not meet the absorption time window, as it is known in the art,for an absorbable suture. Indeed, in subsequent U.S. Pat. Nos. 4,027,676and 4,201,216 it is pointed out that the disclosure of linear polyestersfor use with absorbable sutures in U.S. Pat. No. 3,942,532 did notconsider that the sutures would not be totally absorbable. On the otherhand, high molecular weight polycaprolactone has been disclosed in U.S.Pat. No. 4,624,256 to provide improved tie down performance and knotsecurity to braided multifilament poly(glycolic acid) sutures under bothdry and wet conditions. Thus, the art clearly demonstrates theusefulness of polycaprolactone as a coating for sutures in terms oftie-down performance and knot security. However, the use of anabsorbable polymer must be matched with its allowable time window forcomplete absorption for a given application. Thus there is a need to beable to regulate the in vivo absorption profile of absorbable polymersto meet the criteria of specific applications.

An object of the invention is to increase the in vivo absorption rate ofpolycaprolactone by blending it with crystallization modifiers thatreduce the amount of crystallinity in the polymer. Thus its rate ofhydrolysis and subsequent mass loss can be regulated in order to meetthe needs of a specific application. A further object of the inventionis to provide an absorbable coating for absorbable sutures which meetsthe time window of complete absorption within one year of surgery andprovides good tie-down performance under both dry and wet conditions. Anadditional object of the invention is to provide a controlled absorbablematrix for the controlled release of chemical for pharmaceutical agents.

SUMMARY OF THE INVENTION

The present invention is directed toward an absorbable coating for asurgical suture comprising a homopolymer of .di-elect cons.-caprolactoneand a crystallization modifier. The suture is preferably an absorbablesuture. The crystallization modifier might be either a crystalline fattyacid or a crystalline ester of a fatty acid. Preferably, thecrystallization modifier is a crystalline ester of a fatty acid.Particularly suitable crystallization modifiers are crystalline estersof fatty acids which are saturated C₁₂ -C₁₈ fatty acid esters ofpolyhydric alcohols. Preferably, the polyhydric alcohols might beglycerol, ethylene glycol or propylene glycol.

The coating composition includes a range from about 95 to about 5% byweight of the homopolymer of .di-elect cons.-caprolactone and a range offrom about 5 to about 95% by weight of the crystallization modifier. Inone composition, the homopolymer of .di-elect cons.-caprolactone rangesfrom about 70 to about 30% by weight and the crystallization modifierranges in weight from about 30 to about 70%. In a specific composition,the homopolymer of .di-elect cons.-caprolactone and the crystallizationmodifier are each about 50% by weight. The homopolymer of .di-electcons.-caproalctone has a molecular weight of at least about 1,000 and amolecular weight range of preferably from about 15,000 to about 40,000.

Also included within the scope of the invention is an absorbable blendcomprising a homopolymer of .di-elect cons.-caprolactone and acrystallization modifier. The present invention further includes anabsorbable surgical suture comprising at least one filament ofpoly(glycolic acid) coated with an absorbable coating which comprises ahomopolymer of .di-elect cons.-caprolactone and a crystallizationmodifier. The suture further comprises a copolymer having at least about85% glycolic acid units.

The invention further embodies an absorbable controlled release matrixcomprising a blend of a homopolymer of .di-elect cons.-caprolactone anda crystallization modifier. The matrix further includes either achemical or a pharmaceutical agent. The matrix crystallization modifiermight either be a crystalline fatty acid or a crystalline ester of afatty acid, preferably the latter. Suitable crystallization modifiersare crystalline esters of fatty acids which are saturated C₁₂ -C₁₈ fattyacid esters of polyhydric alcohols, preferably such as glycerol,ethylene glycol or propylene glycol. The matrix homopolymer of .di-electcons.-caprolactone ranges in weight from about 95 to about 5% by weightof the blend and the crystallization modifier ranges in weight fromabout 5 to about 95% by weight of the blend.

In a further embodiment, the invention includes an absorbable blendcomprising a copolymer of at least about 80% by weight of .di-electcons.-caprolactone and corresponding remainder weight of anotherabsorbable monomer, and a crystallization modifier. The blend furtherincludes either a chemical or pharmaceutical agent.

The invention further embodies a method for effecting the rate ofabsorption of polycaprolactone comprising the step of blending ahomopolymer of .di-elect cons.-caprolactone and a crystallizationmodifier. The absorption rate increases as the blend ratio of thecrystallization modifier to the homopolymer of .di-electcons.-caprolactone increases.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The in vivo absorption rate of polycaprolactone can be increased byblending the polymer with crystalline fatty acid esters of polyhydricalcohols, which function as crystallization modifiers. Furthermore, therate of this absorption can be regulated by control of the amount ofadded crystalline modifier. The blending of these fatty acid esters withthe polycaprolactone do not however adversely effect its excellentcoating properties. Thus the polycaprolactone-fatty acid ester blends ofthe present invention are an excellent absorbable coating for absorbablesutures such as those of braided poly(glycolic acid). Moreover, theseblends can be used in the controlled release of chemical orpharmaceutical agents.

The rate of hydrolysis and subsequent mass loss in the hydrolyticdegradation of polycaprolactone has been increased through the blendingof the polycaprolactone with a crystallization modifier. In essence, thecrystallization modifiers have been found to reduce the amount ofcrystallization in the polycaprolactone and to also retard the filmforming ability of polycaprolactone that has been cast from solution ina volatile solvent. Remarkably, the blending of the polycaprolactonewith the crystallization modifiers of the present invention does notadversely affect the desired properties of the polycaprolactone. Thecrystallization modifiers of the present invention are themselvescrystalline in nature and readily form homogeneous solid blends withpolycaprolactone either by casting from a solution of each or bypreparation from a melt. This suggests an intimate interaction andcompatibility between the polycaprolactone and the non-polymercrystallization modifiers.

In this invention, both homopolymers and copolymers of .di-electcons.-caprolactone are suitable for blending with a crystallizationmodifier. Homopolymers of .di-elect cons.-caprolactone should have aminimum molecular weight of at least about 1000. However, there is nomaximum limit that is applicable to the homopolymer. A variety ofmolecular weights in polycaprolactones is commercially available fromUnion Carbide Corporation under the TONE brand name. For example, lowermolecular weight polycaprolactones are available as TONE Polyols, whilehigher molecular weight polycaprolactones are available as TONE PCL-300and TONE PCL-700, which have weight average molecular weights of 15,000and 40,000, respectively, as reported by the manufacturer. Copolymers of.di-elect cons.-caprolactone are those synthesized from at least about80% by weight of the .di-elect cons.-caprolactone monomer and thecorresponding remainder of another absorbable monomer. The copolymerscould be either random or block copolymers. Absorbable monomersconsistent with these copolymers include glycolic acid, lactic acid, andother aliphatic hydroxycarboxylic acids which are usually polymerizedfrom their corresponding lactones, that is, glycolide, lactide, etc.Such copolymers, which contain a high percentage by weight ofpolycaprolactone segments, can have their in vivo absorption ratesincreased by their blending with crystallization modifiers.

In this invention, crystallization modifiers have been found whichaffect the crystallinity of polycaprolactone and its film formingability. The preferred crystallization modifiers have been found to besaturated C₁₂ -C₁₈ fatty acid esters of polyhydric alcohols. Polyhydricalcohols useful in this invention are, for example, glycerol, ethyleneglycol and propylene glycol. Commercial sources of these materials,which are often a mixture of compounds like glycerol monostearate (alsocontains glycerol palminate for instance), are suitable in thisinvention. Such esters are crystalline in nature, that is, showcharacteristic X-ray powder diffraction patterns of crystalline matter.It is believed that this inherent crystallinity of these fatty acidesters allows for a crystalline interaction with the "semi-crystalline"polycaprolactone, which produces a lower net crystallinity in the blend.Furthermore, that this disruption in crystallinity in the net blend andin the constituent polycaprolactone is responsible for the disruption infilm forming ability in the polycaprolactone. Thus, two factors ofcritical importance in the rate of hydrolytic degradation and subsequentmass loss of polycaprolactone can be controlled by the addition of thecrystallization modifiers of this invention. Another importantcharacteristic of these crystallization modifiers is that they are waterinsoluble, but enzymatically degradable. Therefore, the crystallizationmodifiers will not be rapidly leached out of their crystallineinteraction with the polycaprolactone and can prevent there-crystallization of the polycaprolactone as it is subject tohydrolytic degradation in its molecular weight.

X-ray powder diffraction spectra have been taken on polycaprolactone-700(PCL-700) (Union Carbide), glycerol monostearate (GMS) pure (StepanChemical Co.), physical mixtures of the two components, and blends ofthe two components. The physical mixture of the two components wasprepared by mixing equal amounts of powdered PCL-700 and GMS together atroom temperature. The blends were prepared for the diffractionexperiments by first dissolving the two solutes in a methylenechloride/methanol solvent to give about a 10% by weight solution. Next,the solvent was evaporated to leave the solid blend, which was carefullyground with a mortar and pestle to produce uniform powder. Diffractionpatterns were recorded in the range of 2 θvalues of 10° to 30° with apowder diffractometer using copper K∝ radiation. Maximum diffractionintensities were observed in this range for the polycaprolactone, theglycerol monostearate, the physical mixture, and the respective blends.The total area underneath each diffraction pattern was quantified, thenscaled to a relative area based upon the physical mixture having an areavalue of 100. The relative area for each sample is a measure of itstotal crystallinity. A comparison of the relative areas under thediffraction patterns in this range is given in Table 1.

                  TABLE I                                                         ______________________________________                                                                   % DECREASE                                                                    IN TOTAL                                           COMPOSITION   RELATIVE AREA                                                                              CRYSTALLINITY                                      ______________________________________                                        physical mixture                                                                            100          --                                                 50% PCL + 50% GMS                                                             blend 50% PCL +                                                                             65           35%                                                50% GMS                                                                       blend 33% PCL +                                                                             56           44%                                                67% GMS                                                                       blend 20% PCL +                                                                             45           55%                                                80% GMS                                                                       ______________________________________                                    

Comparison of the diffraction pattern of a 1 to 1 physical mixture ofpolycaprolactone(PCL) with glycerol monostearate(GMS) to the diffractionpattern of the 1 to 1 blend of the two components, which was prepared asdescribed above, shows a 35% decrease in crystallinity in the blend.Larger decreases in crystallinity occur as the proportion of theglycerol monostearate is increased. Furthermore, it is evident that thecrystallinity is decreased in both components. Thus, an intimateinteraction between the two components is suggested.

A qualitative assessment of the relative film forming ability ofpolycaprolactone versus the blends of this invention was carried out bydecantation of the respective 10% by weight solutions onto a flatsurface and allowing the solvent to evaporate. In this experimentmono-di-glycerides (MDG) (Stepan Chemical Co.) was used as thecrystallization modifier for polycaprolactone-700 (Union Carbide). Theseresults are summarized in Table II and show a dramatic decrease in filmforming ability as the proportion of the crystallization modifier isincreased.

                  TABLE II                                                        ______________________________________                                               COMPOSITION FILM DESCRIPTION                                           ______________________________________                                        100%     PCL           strong, tough, clear                                   90%      PCL + 10% MDG very weak film, opaque                                 70%      PCL + 30% MDG forms white layer, weak                                                       cohesion                                               50%      PCL + 50% MDG forms white solid, weak                                                       cohesion                                               30%      PCL + 70% MDG forms white particulate solid                          10%      PCL + 90% MDG forms white particulate solid                          ______________________________________                                    

The film forming tendencies of the blends of this invention were furtherinvestigated by following coated poly(glycolic) (PGA) suture integrityunder in vitro conditions. For example, size O braided poly(glycolicacid) sutures uncoated, coated with 100% polycaprolactone-700 (UnionCarbide), and coated with a 1 to 1 blend of polycaprolactone-700 (UnionCarbide) and glyceryl monostearate pure (Stepan Chemical Co.) were eachimmersed in buffer solution at a pH of 7.0 in test tubes and placed in aconstant temperature bath at 50° C. The coated sutures had coatingweight pick-ups of 7 and 5% for the PCL-700 and the 1 to 1 blend,respectively. Visual inspection of the sutures was recorded over time.By Day-48 both the uncoated PGA suture and the suture coated with ablend of PCL/GMS had degraded to a lint-like residue. However, the PCLcoated suture was only broken into small rigid segments. This appearanceof the PCL coated suture was unchanged at Day-78 and suggested that thesuture was encapsulated by a strong, tough film of the polycaprolactone.On the other hand, both the uncoated suture and the suture coated with a1 to 1 blend of PCL/GMS exhibited a similar degree of degradation in thesame time frame of 48 days.

Although the primary object of this invention is to influence andregulate the rate of hydrolysis and mass loss in polycaprolactone, thisobjective should not be achieved at the expense of its applicationbenefits. In the case of its application as an absorbable suture coatingit has been found that the coating effectiveness of the various blendsis actually increased over that of 100% PCL. Thus it appears that theblending of polycaprolactone with the crystallization modifiers of thisinvention enhances the softness and pliability of the suture as comparedto a suture coated with only polycaprolactone.

The blends of polycaprolactone and crystallization modifiers of thepresent invention also have application in the controlled release ofchemical and pharmaceutical agents. Indeed, the proportion ofcrystallization modifier to polycaprolactone can be used to regulate therate of release of chemical or pharmaceutical agents. Moreover, theseblends have improved rates of mass loss when compared to matrices of100% PCL. The blending of polycaprolactone with a crystallizationmodifier like glycerol monostearate thus produces an absorbable matrixwith many beneficial attributes. Besides the benefit of regulatedrelease and mass loss, blends of this invention are expected to ingeneral release agents faster than that of 100% polycaprolactone, yetmuch slower than 100% of a crystallization modifier like glycerolmonostearate.

The following illustrate, by way of example, use of an absorbable blendfor an absorbable suture (Example 1) and an absorbable controlledrelease matrix (Example 2).

EXAMPLE 1

A coating solution comprised of the following by weight percent, 5.5%polycaprolactone-700 (Union Carbide), 5.5% mono-di-glycerides (StepanChemical Co.), 9% methanol, and 80% methylene chloride, was used to coatabsorbable braided sutures of poly(glycolic acid) in the size range fromsize 2 to 6/0. A continuous feed of the spooled uncoated suture waspassed for a short time at a fixed rate through the coating solution,then allowed to air dry before winding onto a take-up spool. The coatedsutures showed a dry weight coating pick-up in the range of about 2 to5% depending upon size. The coated suture has excellent handling andtie-down properties under both dry and wet conditions for all sizes.Comparison of the implantation of this sterile coated suture versus thatof the sterile uncoated suture in rats, has shown that the coating doesnot effect the in vivo tensile strength of the suture during thecritical time period of wound healing. Additionally, over a longer timeperiod, both the coated and uncoated sutures exhibited a similar rate ofabsorption. Comparison of the implantation of the sterile coated sutureof this invention versus sterile poly(glycolic acid) sutures coated withonly polycaprolactone 700 in rats, has shown that the coated sutures ofthis invention show complete absorption before those sutures coated withjust polycaprolactone. Furthermore, the coated sutures of this inventionshow complete absorption of suture and coating, well within a timewindow of one year.

EXAMPLE 2

Application of absorbable blends of polycaprolactone and acrystallization modifier as an absorbable controlled release matrix wasdemonstrated by following the in vitro release of methylene blue(Aldrich Chemical Co.) from thin disks of the absorbable matrix.Methylene blue is a water soluble dye and was used to mimic the releaseof a water soluble chemical or pharmaceutical agent from the absorbablematrix. Absorbable controlled release matrices containing methylene bluewere prepared as follows. Portions of solid polycaprolactone-700 (UnionCarbide) and mono-di-glycerides (Stepan Chemical Co.) in relativeproportions of 7 to 3, 1 to 1, and 3 to 7 were heated to about 90° C.and stirred to give homogeneous melts. Exactly 0.4% by weight ofmethylene blue was then mixed into each melt. The melts were then pouredonto a cool plate to form disks 2 mm thick. Immersion of equal amountsof disks of each composition in buffer solution of pH 7.0 at atemperature of 50° C. showed a staggered rate of blue dye release as afunction of disk composition. The rate of dye release increased withincreasing amounts of mono-di-glycerides to polycaprolactone. Moreover,the rates of dye release from the absorbable matrices were greater thanthat of a similarly prepared disk of 100% PCL-700, but lower than thatof similarly prepared disks of mono-di-glycerides.

The present invention has been described herein with specific referenceto the preferred embodiments thereof. However, those skilled in the artwill understand that changes may be made in the form of the inventioncovered by the claims without departing from the scope and spiritthereof, and that certain features of the invention may sometimes beused to an advantage without corresponding use of the other features.

The invention claimed is:
 1. An absorbable controlled release matrix forthe release of a chemical or pharmaceutical agent comprising a chemicalor pharmaceutical agent, a blend of about 95 to 5% by weight of ahomopolymer of .di-elect cons.-caprolactone and about 5 to about 95% byweight of a crystallization modifier selected from the group consistingof crystalline fatty acids and crystalline esters of fatty acids whichare saturated C₁₂ -C₁₈ fatty acid esters of polyhydric alcohols.
 2. Thematrix according to claim 1 wherein said crystallization modifier iscrystalline esters of fatty acids which are saturated C₁₂ -C₁₈ fattyacid esters of polyhydric alcohols.
 3. The matrix according to claim 2wherein said polyhydric alcohols are selected from the group consistingof glycerol, ethylene glycol, and propylene glycol.
 4. The matrixaccording to claim 1 wherein said homopolymer of .di-electcons.-caprolactone has a molecular weight of at least about
 1000. 5. Anabsorbable controlled release matrix for the release of a water-solublechemical or water-soluble pharmaceutical agent comprising awater-soluble chemical or water-soluble pharmaceutical agent, a blend ofabout 95 to 5% by weight of a homopolymer of .di-electcons.-caprolactone and about 5 to about 95% by weight of acrystallization modifier selected from the group consisting ofcrystalline fatty acids and crystalline esters of fatty acids which aresaturated C₁₂ -C₁₈ fatty acid esters of polyhydric alcohols.
 6. Anabsorbable controlled release matrix for the release of a water-solublechemical or water-soluble pharmaceutical agent comprising awater-soluble chemical or water-soluble pharmaceutical agent, a blend ofa copolymer of at least 80% by weight of .di-elect cons.-caprolactoneand corresponding remainder weight of another absorbable monomer, and acrystallization modifier selected from the group consisting ofcrystalline fatty acids and crystalline esters of fatty acids which aresaturated C₁₂ -C₁₈ fatty acids esters of polyhydric alcohols.
 7. Thematrix according to claim 6 wherein said polyhydric alcohols areselected from the group consisting of glycerol, ethylene glycol, andpropylene glycol.